The correlation in echocardiogram to right heart catheterization in identifying pulmonary hypertension as a barrier to liver transplantation.

BACKGROUND: Pulmonary hypertension (PH) and portopulmonary hypertension (POPH) can be limitations towards listing for liver transplantation (LT). Our study evaluates the correlation of right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP) on transthoracic echocardiogram (TTE) compared to mPAP on right heart catheterization (RHC). METHODS: We performed a retrospective review of 723 patients who underwent LT evaluation at our institution between 2012 and 2020. Our cohort consisted of patients with RVSP and mPAP measured on TTE. A Wald t-test and area under the curve analysis were used for statistical analyses. RESULTS: Patients with higher mPAP values on TTE (N=33) did not correlate with mPAP ≥ 35 mmHg on RHC, while patients with higher RVSP values (N=147) on TTE were associated with mPAP ≥ 35 mmHg on RHC. The cutoff value of RVSP ≥ 48 mmHg on TTE was associated with mPAP ≥ 35 mmHg on RHC. CONCLUSIONS: Our data suggest that RVSP compared to mPAP on TTE is a better indicator for mPAP ≥ 35 mmHg on RHC. RVSP can be used as a marker on echocardiography for identifying patients with a higher likelihood of PH being a barrier to LT listing.

Marijuana use and post-transplant complications and non-compliance in liver transplant patients.

BACKGROUND: Liver transplant (LT) is a lifesaving treatment for patients with end stage liver disease. Historically, institutions across the United States have deemed active marijuana use as an exclusion criterion for listing. This study aims to investigate LT outcomes in patients with history of marijuana use prior to LT. METHODS: We performed a retrospective review of 111 patients who tested positive for marijuana on urine drug screen during initial LT evaluation between February 2016 and January 2021. 100 non-marijuana users who underwent LT were cross matched for control. Patient demographics, substance use history, and transplant decisions were recorded. Post-LT variables were also collected up to 1 year post surgery including postoperative infections, issues with non-compliance, and continued substance use. Chi-square analysis was used to assess the association between pre-transplant marijuana use and post-transplant complications. Logistics regression was implemented to measure associations amongst the entire cohort. RESULTS: From 111 marijuana users, 32 (29%) received a transplant. There was no statistical difference in post-LT outcomes between marijuana and non-marijuana users, including incidence of cardiac, respiratory, renal, psychiatric, or neurological complications, as well as readmission rates post-surgery. There were no statistically significant associations between marijuana use with post-transplant bacterial or fungal infections, medication non-compliance, or continued substance use (all p>0.05). Marijuana use was associated with pre-LT tobacco use (p = 0.020). CONCLUSIONS: Our data indicates that marijuana is not associated with increased risk of postoperative noncompliance, other organ complications, infections, or death. As a single factor, marijuana may not need to be a contraindication for LT.

Nutritional Deficiencies and Clinical Practices in Decompensated Cirrhotics With Hepatic Encephalopathy.

Background Hepatic encephalopathy (HE), a major complication of end-stage cirrhosis, is often associated with nutritional deficiencies. We aimed to assess the frequency in which vitamins and zinc were tested for and deficient in our cirrhotic population with HE. Methods We performed a retrospective chart review of 143 patients with decompensated cirrhosis that were seen in a hepatology clinic from January 2020 to May 2021. Patient demographics and decompensations were recorded. Vitamins and minerals that were evaluated included zinc, vitamin B12, folate, vitamin D, and thiamine. Continuous variables were reported as mean ± standard deviation and categorical variables were calculated as frequency percentages. Results Out of 143 patients, 73 were found to have HE. Out of 73, 33 were male, and the average MELD was 15.5 ± 6.3. 44% of patients had NASH cirrhosis, and 30% had alcoholic cirrhosis. Of the minority of patients that had their nutrient levels checked, 17/23 (74%) were deficient in zinc (<60 mcg/dL). 75% of patients were deficient in thiamine. 2/34 (6%) were deficient in folate (<5.9 ng/mL), 2/10 (20%) in vitamin D (<20 ng/mL), and 2/47 (4%) in B12 (<300 pg/mL). Conclusion Nutritional deficiencies are common in cirrhotics with HE. Further studies are needed to determine if routine testing and treatment for vitamin and Zinc deficiencies would have a positive impact on the clinical trajectory of HE.

Liver stiffness and prediction of cardiac outcomes in patients with acute decompensated heart failure.

BACKGROUND: In acute decompensated heart failure (ADHF), noninvasive markers that predict morbidity and mortality are limited. Liver stiffness measurement (LSM) increases with hepatic fibrosis; however, it may be falsely elevated in patients with ADHF in the absence of liver disease. We investigated whether elevated LSM predicts cardiac outcomes in ADHF. METHODS: In a prospective study, we examined 52 ADHF patients without liver disease between 2016 and 2017. Patients underwent liver 2D shear wave elastography (SWE) and were followed for 12 months to assess the outcomes of left ventricular assist device (LVAD), heart transplant (HT) or death. RESULTS: The median LSM was elevated in patients who received an LVAD or HT within 30-days compared to those who did not (median [IQR]: 55.6 [22.5 - 63.4] vs 13.8 [9.5 - 40.3] kPa, p = .049). Moreover, the risk of composite outcome was highest in the 3rd tertile (> 39.8 kPa compared to 1st and 2nd combined, HR 2.83, 95% CI 1.20- 6.67, p = .02). Each 1-kPa increase in LSM was associated with a 1%-increase in the incidence rate of readmissions (IRR 1.01, 95% CI 1.00-1.02, p = .01). CONCLUSIONS: LSM may serve as a novel noninvasive tool to determine LVAD, HT, or death in patients with ADHF.

Inflammation increases the development of depression behaviors in male rats after spinal cord injury.

Following spinal cord injury, 18-26% of patients are diagnosed with depressive disorders, compared to 8-12% in the general population. As increased inflammation strongly correlates with depression in both animal and human studies, we hypothesized that the immune activation inherent to SCI could increase depression-like behavior. Thus, we proposed that reducing immune activation with minocycline, a microglial inhibitor, would decrease depression-like behavior following injury. Male Sprague-Dawley rats were given minocycline in their drinking water for 14 days following a moderate, mid-thoracic (T12) spinal contusion. An array of depression-like behaviors (social activity, sucrose preference, forced swim, open field activity) were examined prior to injury as well as on days 9-10, 19-20, and 29-30 post-injury. Peripheral cytokine levels were analyzed in serum collected prior to injury and 10 days post-injury. Hierarchical cluster analysis divided subjects into two groups based on behavior: depressed and not-depressed. Depressed subjects displayed lower levels of open field activity and social interaction relative to their not-depressed counterparts. Depressed subjects also showed significantly greater expression of pro-inflammatory cytokines both before and after injury and displayed lower levels of hippocampal neurogenesis than not-depressed subjects. Intriguingly, subjects who later showed depressive behaviors had higher baseline levels of the pro-inflammatory cytokine IL-6, which persisted throughout the duration of the experiment. Minocycline, however, did not affect serum cytokine levels and did not block the development of depression; equal numbers of minocycline versus vehicle-treated subjects appeared in both phenotypic groups. Despite this, these data overall suggest that molecular correlates of inflammation prior to injury could predict the development of depression after a physical stressor.

EGFR inhibition triggers an adaptive response by co-opting antiviral signaling pathways in lung cancer.

EGFR inhibition is an effective treatment in the minority of non-small cell lung cancer (NSCLC) cases harboring EGFR-activating mutations, but not in EGFR wild type (EGFRwt) tumors. Here, we demonstrate that EGFR inhibition triggers an antiviral defense pathway in NSCLC. Inhibiting mutant EGFR triggers Type I IFN-I upregulation via a RIG-I-TBK1-IRF3 pathway. The ubiquitin ligase TRIM32 associates with TBK1 upon EGFR inhibition, and is required for K63-linked ubiquitination and TBK1 activation. Inhibiting EGFRwt upregulates interferons via an NF-κB-dependent pathway. Inhibition of IFN signaling enhances EGFR-TKI sensitivity in EGFR mutant NSCLC and renders EGFRwt/KRAS mutant NSCLC sensitive to EGFR inhibition in xenograft and immunocompetent mouse models. Furthermore, NSCLC tumors with decreased IFN-I expression are more responsive to EGFR TKI treatment. We propose that IFN-I signaling is a major determinant of EGFR-TKI sensitivity in NSCLC and that a combination of EGFR TKI plus IFN-neutralizing antibody could be useful in most NSCLC patients.

Efficacy of EGFR plus TNF inhibition in a preclinical model of temozolomide-resistant glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common primary malignant adult brain tumor. Temozolomide (TMZ) is the standard of care and is most effective in GBMs that lack the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Moreover, even initially responsive tumors develop a secondary resistance to TMZ and become untreatable. Since aberrant epidermal growth factor receptor (EGFR) signaling is widespread in GBM, EGFR inhibition has been tried in multiple clinical trials without success. We recently reported that inhibiting EGFR leads to increased secretion of tumor necrosis factor (TNF) and activation of a survival pathway in GBM. Here, we compare the efficacy of TMZ versus EGFR plus TNF inhibition in an orthotopic mouse model of GBM. METHODS: We use an orthotopic model to examine the efficacy of TMZ versus EGFR plus TNF inhibition in multiple subsets of GBMs, including MGMT methylated and unmethylated primary GBMs, recurrent GBMs, and GBMs rendered experimentally resistant to TMZ. RESULTS: The efficacy of the 2 treatments was similar in MGMT methylated GBMs. However, in MGMT unmethylated GBMs, a combination of EGFR plus TNF inhibition was more effective. We demonstrate that the 2 treatment approaches target distinct and non-overlapping pathways. Thus, importantly, EGFR plus TNF inhibition remains effective in TMZ-resistant recurrent GBMs and in GBMs rendered experimentally resistant to TMZ. CONCLUSION: EGFR inhibition combined with a blunting of the accompanying TNF-driven adaptive response could be a viable therapeutic approach in MGMT unmethylated and recurrent EGFR-expressing GBMs.